Last December the once-promising direct renin inhibitor aliskiren (Rasilez, Tekturna) suffered a fatal setback with the early termination of the ALTITUDE trial. The trial was stopped when the Data Monitoring Committee (DMC) found an increased risk for non-fatal stroke, renal complications, hyperkalemia, and hypotension in patients taking aliskiren after 18-24 months.

At the ESC in Munich ALTITUDE investigator Hans-Henrik Parving presented the first detailed but preliminary results from the trial, which compared aliskiren to placebo in 8,561 type 2 diabetics at high risk for cardiovascular and renal complications already receiving single RAAS blockade.

After 32 months of followup, the composite endpoint (CV death, resuscitated death, MI, stroke, unplanned hospitalization for heart failure, onset of end-stage renal disease or doubling of baseline creatinine) was not significantly different between the two groups, though Parving noted that the numbers went in the wrong direction for aliskiren, including a trend suggesting more strokes associated with the treatment drug:

Aliskiren-treated patients also had higher potassium levels and were more likely to develop hyperkalemia, hypotension, and diarrhea.

Republished with permission from CardioExchange, a NEJM group publication.

Here is the press release from the ESC:

Median follow-up results from the ALTITUDE study, stopped prematurely in December 2011

Munich, Germany – 26 August 2012: Preliminary results from the Aliskiren Trial in Type 2 Diabetes Using Cardio-Renal Endpoints (ALTITUDE) do not support administration of aliskiren on top of standard therapy with renin-angiotensin-aldosterone system (RAAS) blockade in type 2 diabetics at high risk of cardiovascular and renal events, according to Professor Hans-Henrik Parving from Rigshospitalet, University of Copenhagen, Denmark. Presenting results from the study today, he said the treatment “may even be harmful”.

The ALTITUDE trial was stopped prematurely in December 2011 on recommendation of the data monitoring committee after it found an increased occurrence of side effects and continuation of the study was deemed “futile”. The study had been investigator initiated to determine whether use of the direct renin inhibitor aliskiren would improve prognosis by reducing fatal and non-fatal cardiovascular and renal events in type 2 diabetics at high risk of these complications. Macro- and microvascular complications of type 2 diabetes are augmented in those with concomitant kidney and/or cardiovascular disease.

ALTITUDE was an international double-blind study in 8561 subjects randomised to aliskiren 300 mg once daily or placebo on top of single RAAS blockade. The primary outcome measure was time to first event for the composite endpoint of cardiovascular death, resuscitated death, myocardial infarction, stroke, unplanned hospitalisation for heart failure, onset of end-stage renal disease or doubling of baseline creatinine.

2 comments

Why Aliskiren Failed To Gain ALTITUDE ? Because it was misfired from the launching pad itself.

A detailed and critical review of the design and randomization of this study revealed numerous flaws in the choice of the diabetic patients with normal blood pressure, high normal potassium and creatinine levels, subjecting them to a second potent RAAS blocker which brings down the blood pressure as its effect and not its adverse effect.

This clinician has treated hundreds of diabetic, hypertensive patients with aliskiren along with other RAAS blockers with appropriate precautions and clinical judgment, but not following any protocol or algorithm and did not encounter the untoward side effects, as seen in the ALTITUDE study. It is not just the final results of any study but how and why it happened also matters.

I hate to quote the common adage “garbage in and garbage out”! It is sad that such a promising drug got a bad wrap as a result of the “implosion” of this study without reaching its appropriate ALTITUDE.

Who will accept the blame, one would wonder, the drug, the study or the investigators?

Aliskiren may not be the problem. It is likely that if an ACEI or ARB had been added to aliskiren (rather than the other way round) the results would have been the same. In other words, side effects are more likely to occur with dual renin-angiotensin system blockade in which the system is blocked by about 99%, than with single renin-angiotensin system blockade in which the system is blocked by only 90%.

The important point is that renin-angiotensin system blockade may add more risk than reward when given to sodium depleted patients. Some of the type 2 diabetics at high risk for cardiovascular and renal complications that were enrolled in the ALTITUDE trial may have been sodium depleted because such patients are usually also treated with natriuretic drugs. In the setting of sodium depletion the circulating renin-angiotensin system becomes much more important. High PRA levels work to prevent blood pressure from falling too low, i.e. below the point where blood flow to vital organs is auto regulated. They also sustain GFR levels via efferent vasoconstriction. Thirdly, they stimulate the higher levels of aldosterone that are needed to secrete potassium in the distal tubule in the setting of sodium depletion.

Thus, when sodium depleted patients have their circulating renin-angiotensin system more effectively blocked, hypotension, deteriorating GFR levels, and hyperkalemia are more likely to occur – all of which were reported as adverse events in patients who received a second anti-renin system drug (aliskiren) on top of an ACEI or ARB during the ALTITUDE trial.